Method of making 4, 5-dihydroimidazoles



Patented May 23, i950 METHOD OF MAKING 4,5-DIHYDRO- HWIDAZOLES Henry L. Merrill, Clayton, Mo., assig'nor to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware No Drawing. Application February 13, 1946, Serial No. 647,429

(01. zen-309.6)

14 Claims. 1

This invention relates to a method of preparing 4,5-dihydroimidazoles and in particular 4,5- dihydroimidazoles substituted in the 2-position.

The preparation of 4,5-dihydroimidazoles using monocarboxylic acid esters and ethylenediamine according to the literature requires a number of operations. The first operation is the acylation of ethylenediamine to form a monoamide, using, for example, the methyl or ethyl ester of the desired acid as the acylating agent. The amide, after separation from excess ethylenediamine and the alcohol formed in the reaction is thereafter cyclized in a separate operation by treatment with lime for 12 to 18 hours at a temperature in the range of approximately 220-230 C. The 4,5- dihydroimidazole thus formed is separated from the lime by extraction with anhydrous methanol or ethanol. The extract is subsequently distilled to remove the solvent and the 4,5-dihydroimidazole is thereafter recovered by distillation. Besides requiring a number of operations, the

process described in the literature leaves much to be desired in the yield of the 4,5-dihydro- 'imidazole and in the efiiciency of the operation from the standpoint of the proportions of starting materials employed in the reaction and the large number of operations involved.

One of the objects of the present invention is ..to provide an improved process for making 4,5-dihydroimidazoles whereby the transition from ethylenediamine to 4,5-dihydroimidazole is accomplished in one operation.

A further object is to provide an improved process of making 4,5-dihydroimidazoles whereby the mono-acylation of ethylenediamine and the cyclization of the monoamide are accomplished in one operation to provide a reaction mixture from which the 4,5-dihydroimidazole may be recovered by fractional distillation.

" Other objects will become apparent from the following description and examples.

j I- have discovered that when methyl or ethyl esters of monocarboxylic organic acids of higher molecular weight than acetic acid are refluxed with anhydrous ethylenediamine, or ethylenediamine containing not more than approximately 10% of water, with removal of the methyl or ethyl alcohol as formed, the mono-acylation of ethylenediamine and the subsequent cyclization of the monoamide can both be accomplished in a single operation and the 4,5-dihydroimidazole maybe recovered directly from the reaction mixture by fractional distillation after stripping off residual ethylenediamine. The yield of the de-' sired product by the process of invention is very satisfactory and in many instances is substantially better than the yields obtainable by the processes described in the literature.

The apparatus employed in practicing the process of the present invention may desirably consist of a reaction vessel, equipped with suit! able heating means, for example a steam jacket, a G-plate column equipped with a total condensation stillhead and a controlled take-over. Any suitable variations of this apparatus may be employed. The removal of the alcohol formed in the process ofthe present invention may be accomplished continuously, for example by taking forward alcohol from the column as the alcohol is formed. The alcohol removal may also be accomplished intermittently during the course of the reaction, for example by allowing the alcohol formed to accumulate in the refluxing vapors, periodically taking forward the alcohol formed and thereafter repeating this cycle, all during the course of reaction.

In place of the methyl or ethyl esters, the esters of higher alcohols may be employed, for example isopropyl, normal propyl, secondary butyl, tertiary butyl or tertiary amyl alcohols. It is essential in the process of the present invention that the alcohol formed during the reaction be removed during the course of the reaction and desirably at the time it is formed. Consequently, it is necessary that a suificiently wide difference between the boiling point of the alcohol and the boiling point of ethylenediamine be established. For that reason, the ester em-; ployed is desirably selected from among those derived from an alcohol having a boiling point of at least 1516 C. lower than the boiling point of ethylenediamine, i. e. below approximately 102 C. I have found the use of the methyl esters desirable for purposes of economy, although the ethyl, isopropyl, normal propyl, secondary butyl, tertiary butyl or tertiary amyl may also be employed, since these alcohols boil at a point substantially below approximately 102 C.

I have found that by using anhydrous ethylenediamine both the formation of the monoamide and the subsequent cyclization of the amide may be accomplished in a single operation. I have further found that ethylenediamine containing up to approximately 10% of water may be employed in place of anhydrous ethylenediamine provided that suflicient. ethylenediamine is employed to sequester the water initially present as the monohydrate of ethylenediamine and thereby in effect isolate the water from the desired reaction mixture. Moreover, it is necessary topro;

water, at relatively low cost, for example; by;

adding caustic soda to the recovered ethylene diamine to salt out the watch. Ethylenediamine thus recovered and partially dehydrated. can be employed in subsequent batches of 4,5-dihydroimidazoles by the process of my invention at;v a substantially lower cost than would be the; case;

if the ethylenediamine had to be rendered anhy drous before re-use. I have found that the 7 presence of substantially more than 10% of water H in the ethylenediam-ine employed-givesrise; t the need: ion excessively; large quantitiesof ethylenee diamine to provide. sufficient; ethylenedianiine to: sequester as the monohydratethe. larger amounts of water. .However, I have found that;it.

economically feasible tov operatetheprocessyof; the present invention with ethylenediaminecon-l tainingup to approximately of; water. The ratio of ethylenediamine to esten. based on, anhy-v drous. ethylenediamine, in the initial. reaction mixturev may rangefromslightly more, than 2:11

when anhydrous ethylenediamine; is, employed, to. 8:1 or even higher. A desirable.- range for those. instances in which the/water, content of the, ethylenediamine is not above, approximately 10%.; may be 3:1 to 621, provided; however that the, ratio in the initial mixture. of reactants selected, to: provide sufilcient. ethylenediamine available: for hydration by the water formed in the cycliza,-.

tion of the monoamide. The ratio wi l vary ac;

cording to the water content of: the ethylene.-. diamineandthe proportion of side reaction products formed in each particular instance.

- The ester employed in the process of the: present invention may be. selected from among those derived-from the condensation of an. alcohol havingaboilingpoint below approximately 102 with amonocarboxylic acid having a. molecular.

weight above that of acetic acid... Fonexample, the acid may be an acyclic, cyclic or heterocyclic monocarboxylic acid, including aliphatic, olefinlo, cycle-aliphatic, aryl-aliphatic, aryloxy-aliphatic, heterocyclic-aliphatic, aryl or. heterocyclic mono-t carboxylic acids and ring halogen-substituted derivatives thereof; Illustrative of. the monocarboxylic acids suitable for the: purpose of the present invention are propionic, butyric, valeric, hexanoic, decanoic, dodecanoic, tridecanoic.v tetradecanoic, pentadecanoic, 4-1phenylbutyric,

ut-cyclohexylbutyric, 'p-chlorophenylacetic, di-

chlorophenylpropionic, phenylacetic, cinnamic,v naphthaleneacetic, pyridineacetic, benzoic, nico-,-. tinic, oleic and linoleic acids; I

The following examples will serve. to illustrate the novel process 'ofmy invention. These, examples are to be construed merely as illustrative andnot as limiting theinventionl xamp e A mixture of 592 g. of, anhydrous ethylene-f diamine. and 427.7 por methyl caproate (3-.1 mole ration) was refluxed under a 6-plate column equipped with a total condensation stillheadand a 'controlled take-over. Methyl alcohol formed during the reaction was slowly distilled forward and was taken over at the rate at which it was formed. The reaction mixture was heated in this manner for 13 hours, or until the evolution of methyl alcohol vapors hadceased. The vapors of methyl alcohol were condensed and recovered a, useful material; Residual, unreacted ethylenediamine was stripped from the reaction mixture by fractional distillation. 2.1 amyl 4,5 dihydroimidazole was fractionally distilled from, the, reaction mixture. Yield, 261.3 g (5,63%). Melting point 53-54.6 C. A high boiling fraction (31.4 g.) was thereafter recoyered from, tha= reaction mixture, B. P. 158/34: mm.+225/9 mm. The residue remainingin the fiask weighed 123.7 g.

Example II A mixture of 400 g. of anhydrous ethylenediamine and 350 g. of methyl caprylate was refluxed for 10 hours under 7 a fi-plate column equipped with a total condensation 'sti llheadand a controlled take over. Methyl alcoholformat-i during the reaction wasremovedaccording-to the procedure described in Example I-. The product recovered from the reaction-mixture lay-the precedureof" Example I was 2 -heptyl-4-g5-dihydroi-midazole. Yield, 224.8 g. 60.6%

' Examplellii A mixture: of 1213-.5 g. of: anhydrousethyl'ene... diamiheand 92613 g. of ethyl laurate was refluxed for 21. 5 hours according to. the procedure. de-.

scribed in Example I; The-- product recovered:- from the reactionmixture by the. procedure of Example I: was 2- undecyl=4,5edihydroimidazoliel Yield, 593.8- g. 65.4%).

Example; V

' reflu ed 5. hours. ue er hec ndi iqns d Example A mixture. at} "4 5% a; ie thylenee emiaa. e: tain ne2 %wate an maven;

we; Yield; 61.7 e. Wm),

Thereafter Example VIII A mixture of 180 g. of ethylenediamine containing water and 94 g. of methyl 4-cyclohexylbutyrate was refluxed for 19 hours under the conditions described in Example I. The product recovered from the reaction mixture by the procedure of Example I was 2(3-cyclohexylpropyl)-4,5-dihydroimidazole. Yield, 72.3 8, (73%).

Example IX A mixture of 205 g. of anhydrous ethylenediamine and 128 g. of methyl phenylacetate was refluxed for hours under the conditions described in Example I. The product recovered from the reaction by the procedure of Example I was 2-benzyl-4,5-dihydroimidazole. Yield, 85.3 g. (62.6%).

Example X A mixture of 3 moles of anhydrous ethylenediamine and 1 mole of ethyl cinnamate was refluxed for 15 hours under the conditions described in Example I. The product recovered from the reaction mixture by the procedure of Example I was 2- (fi-styryl) -4,5-dihydroimidazole.

Example XI A mixture of 3 moles of anhydrous ethylenediamine and 1 mole of ethyl benzoate was refluxed for 15 hours under the conditions described in Example I. The product recovered from the reaction mixture was 2-pheny1-4,5- dihydroimidazole.

Example XII A mixture of 3 moles of anhydrous ethylenediamine and 1 mole of ethyl oleate was refluxed for 15 hours under the conditions described in Example I. The product recovered by the procedure described in Example I was 2- (8-heptadecenyl) -4,5-dihydroimidazole.

Example XI I I A mixture of 3 moles of anhydrous ethylenediamine and 1 mole of ethyl nicotinate was refluxed for 15 hours under the conditions described in Example I. The product recovered by the procedure of Example I was 2-(3- pyridyl) -4,5-dihydroimidaz0le.

The foregoing examples are to be construed as being merely illustrative of the process of the present invention and it is to be understood that other esters of the monocarboxylic acids described therein as well as esters of other monocarboxylic acids may also be employed in the process of my invention. It is also to be understood that my invention is not to be limited to the particular conditions described in the aforescribed examples but that various modifications and alternatives may be practiced which provide essentially the reaction conditions described hereinabove for the accomplishment of the cyclization of the ethylenediamine derivative formed in situ and that these variations and modifications are contemplated as being within the scope of the present invention.

I claim:

1. A process of preparing 4,5-dihydroimidazoles consisting of heating an ester formed by the esterification of a monocarboxylic acid having a molecular weight greater than 60 and a monohydric alcohol having a boiling point below approximately 102 C. with an excess of ethylenediamine containing less than approximately'10% 6.. of water, simultaneously fractionally distilling ofi the alcohol formed during the course of the reaction, thereafter removing residual ethylenediamine from the reaction mixture and subsequently recovering the 4,5-dihydroimidazole from the reaction mixture, the ratio of ethylenediamine to ester in the reaction mixture initially being selected to provide sufficient ethylenediamine available for chemical hydration by the water evolved during the cyclization of the monoamide.

2. A process of preparing 4,5-dihydroimidazoles consisting of heating an ester formed by the esterification of a monocarboxylic acid having a molecular weight greater than and a monohydric alcohol having a boiling point below approximately 102 C. with an excess of ethylenediamine containing less than approximately 10% of water,

continuously fractionally distilling off the alcohol formed during the course of the reaction, thereafter removing residual ethylenediamine from the reaction mixture and subsequently recovering the 4,5-dihydroimidazole from the reaction mixture, the ratio of ethylenediamine to ester in the reaction mixture initially being selected to provide sufficient ethylenediamine available for chemical hydration by the water evolved during the cyclization of the monoamide.

3. A process of preparing 4,5-dihydroimidazoles consisting of heating an ester formed by the esteriflcation of a monocarboxylic acid having a molecular weight greater than 60 and a monohydric alcohol having a boiling point below approximately 102 C. with an excess of ethylenediamine containing less than approximately 10% of water, intermittently fractionally distilling off the alcohol formed during the course of the reaction un-- til formation of the alcohol in the reaction mixture ceases, thereafter removing residual ethylenediamine from the reaction mixture and subsequently recovering the 4,5-dihydroimidazole from the reaction mixture, the ratio of ethylenediamine to ester in the reaction mixture initially being selected to provide suflicient ethylenediamine available for chemical hydration by the water evolved during the cyclization of the monoamide.

v 4. A process of preparing 4,5-dihydroimidazoles consisting of heating an ester formed by the esterification of a monocarboxyllc acid having a molecular weight greater than 60 and a monohydric alcohol having a boiling point below approximately 102 C. with an excess of ethylenediamine containing less than approximately 10% of water, the ratio of ethylenediamine to ester in the initial reaction mixture being in the range of 3:1 to 6:1, provided further that the ratio of ethylenediamine to ester in the reaction mixture initially is selected to provide sufilcient ethylenediamine available for chemical hydration by the Water evolved during the cyclization of the monoamide, simultaneously fractionaliy distilling off the alcohol formed during the course of the reaction, thereafter removing residual ethylenediamine from the reaction mixture and subsequently recovering the 4,5-dihydroimidazole from the reaction mixture.

5. A process of preparing 4,5-dihydroimidazoles consisting of heating an ester formed by the esterification of a monocarboxylic acid having a molecular weight greater than 60 and a monohydric alcohol having a boiling point below approximately 102 C. with an excess of ethylenediamine containing less than approximately 10% of water, the ratio. oflethylenediamine to ester in the initial reactiornmixturebeing m the-rangeot '2zlithis: n:

DZOVidBdEl furtherthat. the. ratioor ethylenedi;

amine to ester in the reaction. mixture initially;

is selected to provide sufficient .ethyl'enediamine', available'forchemical hydration bythe water,- evolved during the cyclization: of-{the monoamide, simultaneously fractionally' distilling off the alcohol formed during the course of the reaction,

thereafter removing residual ethylenediam-ine from the reaction mixture and subsequently: recovering the 4,5-dihydroimidazle fIOm t 'hGrGaQ- tion-mixture: 7

6i A'process of preparing 4,5dihydroimidazolesconsisting of heating an ester formed by theesterification ofa monocarboxylic acid having a molecular weight greater than 60 and a mono hydric alcohol having a boiling point below ap proximately 102: C; with an excess oi anhyd'rousethyl'enediamine, simultaneously fractionally dis-- tilling oi'f the alcohol formed during the course of the reaction, thereafter removing residual ethylenediaminefrom the reaction mixture and subsequently recoveringthe 4,5-dihydroimidazol'e fromthereaction mixture, the-ratio of ethylenediamine to ester in the reaction mixture initially being selected to provide sufficient; ethylenediamine available for chemical hydration by the 7 water evolvedduring the cyclization of themonoamide.

7. A process oi preparing 4,5-dihydroimidazoles consisting of heating an ester formed by the esterification ofanacyclic monocar-boxylic acid. having a molecular weight greater than 60 and" a monohydric alcohol having a boiling point be-v low approximately- 102 C; with an excess of ethylenediamine containing less than approxia mately 10% of water, simultaneously fractionallydistilling off'the alcohol formed during the 'course'ofthe reaction, thereafter removing resid ual' ethylenediamine from the reaction mixture and subsequently recovering thei,5'-dihydroimidazolefrom the reaction mixture, the ratio of ethylenediamine'to' esterin the a reaction mixture initially being selected-to provide suflicientethyl enediamine available for chemical hydration by the water evolved during the: cyclization ot the: monoamide.

8; A process of preparing 4,5-d-ihydroimidazol'es consisting of heating an ester formed by the. esterification of'a cyclic monocarboxylic acid:

swam:

subsequently recoveringtheutfi-dihydroimidazole from thereaction mixture, the. ratio of ethylenediainine to. ester. in, the reaction mixtureinitially being selected to provide sufficient ethylened'i'f, amine availablefor chemical hydrationiby the, water evolvedlduring the.cyclizationoi the mono amide.

19,. A process oiipreparing 4,5-dihydroimidazoles; consisting of heating an ester formed by, the, esteriflcation of an aryl aliphatic monocarboxylic' acid and a monohydric alcohol having a boiling point below approximately .102 C. with an excess of 'ethylenediamine containing lessthan approxie;

mately. 10% of-water, simultaneously fractionallya distillingofit thealcohol formed; during the course. of the.- reaction, thereafter. removing. residual;

ethylenediamine. from the 1 reaction. mixture. and;-

subsequently recovering the 4,5-dihydroimi'dazole from the reaction mixture,.the ratio of ethylene diamine to ester in. thereaction mixture initially being selectedv to provide sufficient ethylene-V dianiine available for chemical hydrationbythe" water. evolvedduring the cyclizationoi the mono amide. w

11'. A process ofg' preparing Z-undecyl l,5f-r;li

hydroimid'azole consisting of heating an esterformed by the esteriilcationotlauric acid and a monohydric alcohol having afboiling point below approximatelyililzi C; withanexcess otxethylentdiamine containing :IBSSithSJl: approximately; 1ll.%-..

otwaten. simultaneously iractionally distilling; off:- thealcohol? formed. during; the course of; the;

reaction, thereafter removing residual ethylentm diamine from the reaction mixtures and subserquently recovering 2eundecyl-4,5-dihydroimidazole from the reaction mixture, the ratio of ethylenediamine to; ester inethe reactiommixture initially being selected-:- to provide sufiicientf;

ethylenediamineiavailablesfor chemicaihydraticn:

by water evolved: during, the( cyclization, oiwt-he;-

monoamide.

12. A process of preparingfle(Si-heptadecenylhl ej-dihydroimidazole consisting of heating an ester formed by the-esterification of oleic acid and a monohydricalcoholhaving a boiling point below approximately 102" C. with an excess; oi

and amonohydric alcoholhavi-ng. a boiling point- 7 below approximately 102 6; with an. excess of.

ethylenediamine containing less than approxi-i mately 10% of water, simultaneously fraction-- allydistilling: ofi the alcohol formed: during the.

course oi the reaction, thereafter removing residual ethylenediamine from the reaction mixture and subsequently recoveringthe ig5-dihydroimid' azol'e from the: reaction mixture, the ratio. of"

ethylenediaminetoester in the reaction mixture ethylenedi'amine containing less than approxi? mately 10%l oi water, simultaneously. fractionally' distillingofi the alcohol'formed during the COlll sci; of the reaction, thereafter. removing residual ethylenediamlneifrom the reactionmixture and" subsequently discovering the, 2,-(8f-heptadecem.

nyl).e4,5-dihydroimidazole from the reaction mixture, the ratio, of, ethylenediamine to ester:-

in the. reaction mixture initially being selected to provide suflicientethylenediamine,available for chemical hydration by the water. evolved during; the cyclization. of themo'noamide,

13. A. process; of. preparing. zebenzyl ij dihxdroimidazole. consisting. of." heating an ester; formedby; the. esterification oi phenylacetic afcidfj and: a.- monohydricvalcohol' having a. boiling, point belowapproximately.- 102 C. with an. excess of;

' ethyiehcdiamine. containing less than, approxie.

mately 10% of water, simultaneously i'ractio'nall'y. distilling. off. the alcohol, formed during the course. of the reaction thereafter. removing residual ethylenediamine from the reaction mixtureand' l bfi lfinmi ece ers. h BnZYhah d-roimidazole fromthe reaction.mixturatherati of ethylenediamine; to. ester-1 in the. reaction mix}.

tureQinitially-bcine; Selected. to, provide sufiicientl hylene ia-mine r ilab e f r em al.-hrdra-,; tion byethe Water evolved; during the cyclizat'on,

c sthammicamid e 14. A process of preparing 4,5-dihydroimidazoles comprising heating in the absence of an added dehydrating agent, an ester formed by the ester-- ification of a monocarboxylic acid having a molecular weight greater than 60 and a monohyclric alcohol having a boiling point below approximately 102 C. with an excess of ethylenediamine containing less than approximately 10% of water, simultaneously fractionally distilling off the alcoholf-ormed during the course of the reaction, thereafter removing residual ethylenediamine from the reaction mixture and subsequently recovering the 4,5-dihydroimidazole from the reaction mixture, the ratio of ethylenediamine to REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,267,965 Wilson Dec. 30, 1941 2,418,077 Kyrides Mar. 25, 1947 

1. A PROCESS OF PREPARING 4,5-DIHYDROIMIDAZOLES CONSISTING OF HEATING AN ESTER FORMED BY THE ESTERIFICATION OF A MONOCARBOXYLIC ACID HAVING A MOLECULAR WEIGHT GREATER THAN 60 AND A MONOHYDRIC ALCOHOL HAVING A BOILING POINT BELOW APPROXIMATELY 102*C. WITH AN EXCESS OF ETHYLENEDIAMINE CONTAINING LESS THAN APPROXIMATELY 10% OF WATER, SIMULTANEOUSLY FRACTIONALLY DISTILLING OFF THE ALCOHOL FORMED DURING THE COURSE OF THE REACTION, THEREAFTER REMOVING RESIDUAL ETHYLENEDIAMINE FROM THE REACTION MIXTURE AND SUBSEQUENTLY RECOVERING THE 4,5-DIHYDROIMIDAZOLE FROM THE REACTION MIXTURE, THE RATIO OF ETHYLENEDIAMINE TO ESTER IN THE REACTION MIXTURE INITIALLY BEING SELECTED TO PROVIDE SUFFICIENT ETHYLENEDIAMINE AVAILABLE FOR CHEMICAL HYDRATION BY THE WATER EVOLVED DURING THE CYCLIZATION OF THE MONOAMIDE. 